central nervous system involvement in burkitt's lymphoma - blood

Central Nervous System Involvement

718 BLOOD, VOL. 36, No. 6 (DECEMBER), 1970

in Burkitt’s Lymphoma

By JOHN L. ZIEGLER, AVRUM Z. BLUMING, RICHARD H. Momtow, LEROY FASS AND

PAUL P. CARBONE

Thirty-five of 77 patients (46%) withBurkitt’s lymphoma presented or de-

veloped evidence of central nervous sys-

tem involvement by tumor. Neu-rologic abnormalities included paraple-gia, cranial neuropathy, altered levels of

consciousness and malignant pleocytosis.An analysis of this series disclosed the

following: Paraplegia is a common pre-senting feature of Burkitt’s lymphoma

and is responsive to systemic chemo-therapy. The association of cranial neu-

ropathy and malignant pleocytosis with

facial tumors points to direct tumor ex-tension to intracranial structures (dura-arachnoid) as the pathogenesis of theselesions. Intrathecal chemotherapy tem-porarily reverses malignant pleocytosis

but systemic chemotherapy is requiredto treat cranial neuropathy. A poor prog-nosis follows presentation or developmentof malignant pleocytosis. The limitationsof the current forms of therapy for CNSinvolvement are discussed.

I N PATIENTS WITH BURKITTS LYMPHOMA, central nervous system( CNS ) involvement is a frequent complication which is difficult to treat

and is associated with a poor prognosis.17 Over a period of 23� years, 77 patients

with Burkitt’s lymphoma have been critically evaluated and studied prospec-

tively at the Lymphoma Treatment Centre in Kampala, Uganda. Thirty-five

patients or 46 per cent had neurological abnormalities appearing at some time

during the course of the disease. Sequential observations were made in these

patients following the presentation or development of CNS involvement by

tumor, with special attention paid to the clinical manifestations, analysis of the

cerebrospinal fluid ( CSF ) and the response to intrathecal chemotherapy. The

results of these observations form the basis of this report.

From the Ltimphoma Treatment Centre, Department of Surgery, Makerere Unicersity

Medical School, Kampala, Uganda.Submitted April 20, 1970; revised June 9, 1970; accepted June 10, 1970.

Supported by Contracts PH-43-67-1343 and PH-43-67-47 from the National Cancer

institute, National Institutes of Health, USPHS, Bethesda, Md.

JOHN L. ZIEGLER, M.D.: Director, Lyniphoma Treatment Centre, Makerere University,

Kampala, Uganda; Senior Investigator, Medicine Branch, National Cancer Institute,Bethesda, Md. Avnuxs Z. BLUMING, M.D.: Senior Investigator, Medicine Branch, National

Cancer Institute, Bethesda, Md., and Scientific Advisor, Lyniphoma Treatment Centre,Makerere University, Kampala, Uganda. RICHARD H. MORROW, JR., M.D., M.P.H., F.A.C.P.:

WHO. Senior Lecturer (Epidemiology), Department of Preventive Medicine, Makerere

University Medical School, Kampala, Uganda. Lacnoy FAss, M.D.: Department of Medicine,University of Washington Medical School, Seattle, Wash. formerly Clinical Associate,

Medicine Branch, National Cancer Institute, Bethesda, Md. PAUL P. CARBONE, M.D.: Chief,

Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Md.

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CNS INVOLVEMENT IN BURKITT’S LYMPHOMA 719

Stage Extent of Disease

I Single facial tumor massII Two or more separate facial tumor masses

III Intrathoracic, intra-abdominal, paraspinalor osseous tumor (excluding facial bones)

IV Central nervous system (malignant cells inthe CSF) or generalized bone marrow involvement

Fig. 1.-Clinical Staging of Burkitt’s Lymphoma

MATERIALS AND METHODS

Seventy-seven patients with histopathologically proven Burkitt’s lymphoma were admitted

to the Lymphoma Treatment Centre, Kampala, Uganda between July 1967 and February

1970. The clinical evaluation and treatment regimen have been described previously.7 The

clinical staging criteria are shown in Fig. 1.

Initial treatment consisted of intravenous cyclophosphamide (CTX) #{176}40 mg./Kg. in a

single dose. Patients with a complete clinical response within 2 weeks of treatment were

randomized to no further therapy or to five more doses of CTX (40 mg/Kg. ) at 2-3

week intervals in a clinical trial comparing minimal treatment with prolonged intensive

chemotherapy. Patients with initial partial responses or patients relapsing following single

doses of CTX were treated with the multiple dose regimen. Patients relapsing on CTX

were treated with the following agents: vincristine (VCR)f 1.4 mg./sq. M. intravenously

on day 1 and methotrexate (MTX)t 15 mg/sq. M. orally on days 1-4, followed in a10-14 day interval by cytosine arabinoside ( ARA-C)� 250 mg/sq. M. intravenouslydaily in a 3-day infusion; the sequence of VCRJMTX-ARA-C was administered for two

cycles (cyclic chemotherapy).

A complete neurological examination and lumbar puncture were performed on all

patients on admission and at follow up intervals of 4-6 weeks. Roentgenograms of the

skull and vertebrae, myelography and cerebral arteriography were performed when mdi-

cated. CSF protein was measured using 3 per cent sulfosalicylic acid and cytological

preparations and cell counts were performed according to the method of Skeel et al.8 CSF

was also examined in some cases using a cytocentrifuge; � � cells were centrifuged at 400 rpm

for 10 minutes and stained with Giemsa stain. At the time of initial lumbar puncture, theneedle was left in place while the CSF cytology was examined in an adjacent laboratory; if

malignant cells were present ( malignant pleocytosis ), intrathecal chemotherapy was instilled

and the needle was withdrawn.

Several regimens of intrathecal chemotherapy were employed. Early in the study,

intrathecal chemotherapy consisted of MTX, 10 mg. given weekly for 1-2 doses beyond

the disappearance of malignant pleocytosis. Citrovorum factor,� 5 mg. intramuscularly

every 6 hours for four doses, was begun at the time of instillation. Patients relapsing

following MTX were treated with weekly ARA-C, 10-50 mg. in incremental doses also

administered for two doses beyond normalization of the CSF. Following the experience

with these agents used singly, a sequential cyclic schedule was employed: MTX, 25 mg./

sq. M. with citrovorum, alternating every 4 days with ARA-C, 50 mg/sq. M. for one

complete cycle beyond normalization of CSF and a minimum of two cycles (“intrathecal

cyclic chemotherapy”). More recently, MTX, 15 mg. daily (with citrovorum), has been

#{176}Cytoxan, Mead Johnson Laboratories, Evansville, Ill.

fOncovin, Eli Lilly and Co., Indianapolis, md.tMethotrexate, Lederle Laboratories Div., American Cyanimid Co., Pearl River, N.Y.

§NSC 63878, Ben Venue Laboratories, Bedford, Ohio.

Ishandon Scientific Co., Ltd., London.�fCalcium leucovorin, Lederle Laboratories Div., American Cyanimid Co., Pearl River,

N.Y.




720 ZIEGLER ET AL.

Table 1.-Presenting Neurological Abnormalities in 24 Patientswith Burkitt’s Lymphoma

No. Patients with Malignant Pleocytosis

TotalPresent Absent

Paraplegia

Cranial neuropathy

Altered consciousnessAsymptomatic

3

614

7

21

10824

Total 14 10 24

given for 4 days, and repeated at 2-4 week intervals if necessary. Both MTX and ARA-C

were diluted in 3 ml. of sterile isotonic saline and instilled with several exchanges of CSF

in the syringe.

All chemotherapeutic regimens were established according to specific protocols which

were approved by research committees at Makerere University Medical School and Mulago

Hospital, Kampala, Uganda as well as at the National Cancer Institute, Bethesda, Md.

RESULTS

Patients with neurological involvement have been divided into two groups:

those who presented with neurological abnormalities, and those who developed

abnormalities at some time during their clinical course.

Patients Presenting With Neurologic Abnormalities

Twenty-four of the 77 patients (31% ) had neurological abnormalities noted

at the time they were first seen ( Table 1 ) . The first two columns in Table 1

indicate the presence or absence of malignant pleocytosis in association with

these neurological findings.

Ten patients presented with paraplegia. The neurologic abnormalities in these

patients ranged from mild paraparesis and deep tendon reflex abnormalities

to flaccid paraplegia, urinary and fecal incontinence, and complete loss of

sensation with sensory levels as high as T5. The symptoms were of relatively

rapid onset and the clinical history ranged from 1-4 months in duration. The

CSF in these patients revealed a high protein content ( range 55-1000 mg. %)

but only three patients ( 30% ) had detectable malignant cells with cell counts

of 6, 10, and 10 cells per cu. mm., respectively. CSF cytology of the remaining

seven patients revealed mononuclear inflammatory cells ranging from 3-36

cells per cu. mm. There was no correlation between CSF findings and the

degree of neurologic disability. Lumbar myelography performed in four pa-

tients revealed either a spinal cord block ( ti�vo patients ) or no abnormality

( two patients).

Eight patients presented with cranial neuropathy involving extraocular mus-

des and six had associated malignant pleocytosis. Of the remaining six patients

presenting with neurologic abnormalities, two had evidence of altered con-

sciousness. Four were asymptomatic but were found to have malignant pleocy-

tosis on routine lumbar puncture.

An analysis of the CSF protein, cell counts and differential cytology of the

patients revealed significantly higher protein concentrations in paraplegic





Table 2.-Neurologic Abnormalities Developing in Stage I-Ill Patients

No.Patients

CNS Involvementon Admission

CranialNeuropathy

Alone

Malignant TotalPleocytosis (One

Alone Both or Both)

Presenting

Stage

‘-IIIIIIIII’m

1 119 None

36 None 2 3 6 11

7 Paraplegia 1 3 42 Cranial Neuropathy 2 2

patients. Protein concentrations did not correlate with the degree of malignant

pleocytosis, the presence of cranial neuropathy, or altered consciousness.

Patients with malignant cells in the CSF had a wide range of cell counts and

differential cytology revealed more than 95 per cent of the cells to be Burkitt

lymphoma cells, with rare lymphocytes or monocytes identified. No correlation

was noted between CSF cell counts and the clinical neurologic findings.

Patients Developing Neurologic Abnormalities

Table 2 reviews the occurrence of cranial neuropathy and malignant pleocy-

tosis which developed in patients with stage I-Ill disease on admission

Paraplegia did not develop in any patient after initial presentation. Of 19

stage I-Il patients, only one patient developed malignant pleocytosis. Among

36 stage III patients, 11 developed neurological abnormalities, two with cranial

neuropathy, three with malignant pleocytosis and six with both findings. In

addition, four of seven surviving paraplegic patients developed cranial nerve

palsies and/or malignant pleocytosis. Two patients presenting with ophthalmo-

plegia later developed malignant pleocytosis as shown by follow-up lumbar

puncture. These findings appeared between 4 and 36 weeks ( median 10 weeks)

after initiation of chemotherapy. Most patients were receiving multiple doses of

cyclophosphamide and had been in complete clinical remission up to the time

of neurological relapse. In three patients, the involved cranial nerve was in

the same anatomic region as a recurrent tumor mass. In five patients, however,

there was no palpable or roentgenographic evidence of tumor along the courseof the affected nerve. Most patients had multiple cranial neuropathies. The

nerves most commonly involved were the third ( five patients ) , sixth ( three

patients ) , seventh ( three patients ) , fifth ( two patients ) , ninth ( two patients)

and twelfth ( one patient) cranial nerves.

No consistent temporal relationship was observed in the association of

cranial neuropathy and malignant pleocytosis (eight patients). The finding of

malignant cells in the CSF preceded the occurrence of cranial neuropathy

in three patients, whereas the reverse situation occurred in three. The interval

separating these events did not exceed 4 weeks. In the remaining two patients,

the findings were observed simultaneously.

Cranial neuropathy and malignant pleocytosis on presentation or following

treatment are correlated with presence of facial tumors (Table 3). There is

twice the risk of these neurologic abnormalities developing in patients with

facial tumors than among patients without facial tumors (chi-square test

1 <0.05).




722 ZIEGLER ET AL.

15 15 12

Table 3.-Correlation of Cranial Neuropathy and/or Malignant Pleocytosiswith the Presence of Facial Tumors

Cranial Neuropathy and/orMalignant Pleocytosis Per Cent with

NeurologicalPresent Absent Total Abnormalities

Facial tumor 27 27 54 50

No facial tumor 5 18 23 22

Total 32 45 77

Response to Therapy

Three of the 10 paraplegic patients died within the first week of therapy

and the remaining seven had complete regression of their gross tumor masses

after cyclophosphamide. Four of the seven surviving paraplegic patients had

improvement of neurologic function after therapy. These patients presented

with mild paraparesis, minimal sensory deficit and reflex abnormalities. The

remaming three patients with more severe neurologic dysfunction had slight

or no improvement.

Of eight patients presenting with cranial neuropathy, one died before the

effects of systemic chemotherapy could be assessed and five of the seven

survivors had complete return of function following systemic cyclophos-

phamide.

Seven of eight patients developing cranial nerve palsies were resistant to

further cyclophosphamide but had complete responses to systemic cyclic

chemotherapy (VCR/MTX-ARA-C ) . Patients with involvement of the cx-

traocular muscles showed the most rapid responses, whereas patients with

facial nerve paralysis took longer to improve.

Table 4 summarizes the responses to intrathecal chemotherapy in patients

with malignant cells in the CSF. Five patients treated early in the study re-

ceived intrathecal MTX 10 mg. weekly for four courses and three relapsed

with malignant pleocytosis 4, 15 and 27 weeks from the completion of therapy.

The two remaining patients have remained in remission for 112+ and 119+

weeks with no evidence of recurrent CSF abnormality. All three patients

with relapsing malignant pleocytosis were treated with intrathecal ARA-C

10-50 mg. at weekly intervals with complete responses of 3, 3 and 4 weeks’

duration.

Table 4.-Experience with Intrathecal Chemotherapy in Burkitt’s Lymphoma

No. Patients

Intrathecal Treatment Regimen Treated Complete Response Relapses

Methotrexate

10 mg. weekly x 4 5 5 3Cytosine arabinoside

10-SO mg. weekly X 4 3 3 3

Cyclic chemotherapy 15 13 13

Methotrexate15 mg. daily x 4





REM�SO�#{176}� �

WEEKS IN REMISSION

Intrathecal cyclic chemotherapy with MTX and ARA-C was administered

to 15 patients. Thirteen patients ( 87% ) had complete disappearance of malig-

nant cells from the CSF, usually following the third or fourth dose. The

remission duration of this group of patients is shown in Fig. 2 which reveals

that all patients eventually relapsed with a mean remission duration of 10

weeks from the time of completion of intrathecal therapy. Retreatment of

relapsing patients with the same cyclic regimen resulted in reinduction of

complete but only temporary responses. Thus, a more effective chemotherapeu-

tic regimen was sought.

Eleven patients relapsing after one or more courses of cyclic intrathecal

chemotherapy and four previously untreated patients with malignant pleocy-

tosis were given MTX 15 mg. intrathecally daily for 4 days, with intramuscular

citrovorum factor 5 mg. at 8-hour intervals for 4 days beginning with the first

intrathecal dose. All 11 patients previously treated had complete responses,

but relapses occurred in all patients within 6 weeks of treatment. Of the

four patients without previous intrathecal treatment, one patient relapsed at

3 weeks and the remaining three have been in complete remission after one

course of treatment for 4+, 10 + and 14+ weeks.

Toxicity

Intrathecal chemotherapy was generally well tolerated and few serious

side effects were encountered following over 300 procedures. Nearly all

patients developed an inflammatory pleocytosis and fever which subsided

completely within a week of cessation of intrathecal chemotherapy. A few

patients complained of headache and nausea following lumbar puncture and

two patients experienced grand ma! seizures. No toxic hematologic or gastro-

intestinal side effects could be attributed to any of the intrathecal chemothera-

peutic regimens employed. In two patients receiving daily intrathecal MTX

for 4 days, in whom citrovorum factor was omitted, both stomatitis and

leukopenia developed in the absence of concomitant systemic chemotherapy.

No patient developed meningeal infection.

Survival

Figure 3 compares the survival (life table analysis) from the time of initial

therapy in three groups of patients: those presenting with malignant pleocyto-




724 ZIEGLER ET AL.

100 � mi� ts �thout�7) #{149}

SURVIVING ‘I Developing (16)I � I

40

2D Presenting (14)

0 � � � I . . I

0 20 40 60 80 100 120 140

REEKS FROM INITIAL TREATMENT

Fig. 3.-A comparison of survival in Burkitt’s lymphoma in patients presenting.

developing, and without malignant cells in the cerebrospinal fluid.

sis, those developing malignant pleocytosis, and patients with normal CSF. The

first group has a very poor prognosis with no survivors beyond 34 weeks. The

second group has a slightly more favorable outlook with a survival of 45 per

cent beyond 80 weeks. This curve includes the only two long-term survivorswho are free of disease in the entire group of patients with malignant pleocy-

tosis. Patients without malignant pleocytosis have an excellent prognosis with

72 per cent survival beyond 1 year. The latter analysis includes seven patients

who died within the first week of treatment before full therapeutic benefit

could be achieved. It is important to note that all but two survivors in the

first two groups are living with disease, whereas all surviving patients without

malignant pleocytosis are in complete remission.

The causes of death in four patients presenting with malignant pleocytosis

who died within 1 week of treatment were attributable to widespread tumor

involving the kidneys, gastrointestinal tract, liver and bone marrow.7 Patients

with malignant pleocytosis who survived beyond the first few weeks following

admission died with tumor which had eventually become resistant to systemic

and intrathecal chemotherapy. The causes of death in six of nine patients in

this group were sepsis (five patients) and hemorrhage (one patient). Three

patients died at home with symptoms suggestive of increased intracranial

pressure (headache, coma, convulsions).

DISCUSSION

Central nervous system involvement by Burkitt’s lymphoma is a commonfinding as reported in retrospective clinical and pathological reviews. Franks

reported 31 of 91 (34%) cases, in Kenya, of Burkitt’s lymphoma with evidence

of CNS involvement. The principal clinical features included altered con-

sciousness (36%), paraplegia (29%) and facial palsy (23%). The CSF re-

vealed tumor cells in the five patients who were evaluated. The mean survival

time in this series was 2 months, and Clifford’ has emphasized the difficulty in

successful management of these patients. Both authors postulate that involve-




CNS INVOLVEMENT IN BURKITF’S LYMPHOMA 725

ment of the CNS is the result of direct tumor growth through bone or along

cranial nerves ( particularly the trigeminal) from primary deposits in the

facial bones.

J anota4 reviewed 25 autopsied cases of Burkitt’s lymphoma in Nigeria and

found pathologic evidence of CNS involvement in 21. He noted a high in-

cidence of tumor invasion of the meninges, cranial nerves, spinal cord, spinal

roots and the dura. Also from Nigeria, Odeku and Osuntokun5 reviewed 105

cases of Burkitt’s lymphoma for evidence of CNS involvement and found

neurologic abnormalities in 47 ( 45% ) , comparable to the incidence in our

series. Twenty-three patients presented with CNS involvement and the re-

mainder developed neurologic abnormalities during their clinical course. Le-

sions of the spinal cord were noted in 16 patients and 18 cases of cranial

neuropathy were recorded. The remaining patients had convulsions ( five),

hemiplegia ( two ) , hydrocephalus ( two ) , or evidence of altered consciousness

( three ) . The CSF was examined in 28 cases. Elevated protein levels were the

most frequent finding. Malignant cells were identified in six, although “pleocy-

tosis” was “the second main abnormality noted.” No correlation could he made

between extent of disease and CNS involvement.

The results of the present series agree substantially with the retrospective

studies described above. The incidence of malignant pleocytosis is higher in

our patients, however, probably because of the prospective plan of CSF sur-

veillance in all patients and the careful attention devoted to CSF cytology.

Paraplegia is a well-recognized complication of Burkitt’s lymphoma, and

the clinical and diagnostic features have been adequately described.’T Surgical

decompression of the spinal cord is not recommended, as the paraspinal tumor

responds rapidly to chemotherapy. If spinal cord damage is not irreversible,

substantial neurologic improvement will follow tumor regression.

The pathogenesis of paraplegia by Burkitt’s lymphoma is not yet understood,

although several authors have offered explanations. Cockshott and Evans2 sug-

gest that epidural involvement is the result of direct spread from an osseous

focus or from a paravertebral deposit through neural foramina. Wright6 be-

lieved that cord lesions were ischemic in origin, due to obstruction of the

radicular arteries or anterior spinal artery by retroperitoneal or retropleural

tumor. He was unable to identify, at postmortem, evidence of cord compres-

sion in six of nine paraplegic cases in which extradura! tumor plaques were

noted. It is likely that both mechanisms (cord compression and ischemia)

play a role in the pathogenesis of paraplegia.4 Spinal cord block can be

identified by myelography, and the level correlates with the neurologic find-

ings. Some patients, however, have no abnormality on myelography, but show

neuropathologic evidence of ischemia at postmortem. A cinical-neuropatho-

logical review of autopsied patients in this series is underway and may shed

further light on this question.

Cranial neuropathy and malignant pleocytosis were frequently associated

findings both on admission and during the clinical course. All patients present-

ing with these abnormalities had gross tumor involvement of bone or soft tis-

sues in the region of the affected cranial nerve. This was not true of patients




726 ZIEGLER ET AL.

who developed these findings during their clinical course, although they fre-

quently had facial tumors on admission. Patients in this latter group were usu-

ally in complete clinical remission at the time the cranial neuropathy appeared.

Moreover, cranial neuropathy appeared in patients while receiving multiple

doses of cyclophosphamide and further courses did not affect the lesion,

suggesting drug resistance.7 Subsequent treatment with the \TCR/ MTX-

ARA-C cycle, however, yielded complete neurologic responses, thus indicating

that the cells infiltrating the cranial nerves could be effectively attacked by

other systemic cytotoxic agents.

The pathogenesis of meningeal and cranial nerve invasion by tumor is specu-

lative. From the present series, the significant correlation between facial tumors

and cranial neuropathy and/or malignant pleocytosis points to direct extension

as the most likely route of invasion. Migratory extension to the dura may occur

along nerve or blood vessel sheaths or directly through bone and periosteum.

Once tumor cells invade the dura, penetration to the subarachnoid space is

likely, as has been demonstrated in experimental leukemia in mice.t1’ Blood-

borne spread to the dura, meninges, choroid plexus and brain parenchyrna

( Virchow-Robin spaces ) is possible, but seems unlikely in view of the in-

frequent finding of circulating tumor cells in Burkitt’s lymphoma, and from

experimental evidence of “tissue barriers” in L1210 murine leukemia.#{176}�1

Malignant cells in the CSF could be effectively managed with intrathecal

chemotherapy in most cases, but relapse was a near-constant feature, and

subsequent resistance to intrathecal agents was observed in some patients

given repeated courses of MTX or ARA-C in various combinations. The asso-

ciation between cranial neuropathy and malignant pleocytosis may be a

“feeder-reservoir” system in which a source of malignant cells outside the

subarachnoid space ( and accessible only to systemic chcmotherapeutic agents)

is seeding cells into the CSF via dura-arachnoid connections ( e.g., the exit

of cranial nerves from the brain ) . The cells in the CSF are accessible only to

intrathecal chemotherapeutic agents. Thus, the logical conclusion is to ad-

minister both systemic and intrathecal agents simultaneously in order to avoid

the problems presented by the pharmacologic barriers of the central nervous

system. At the present time, we plan to administer intrathecal MTX or ARA-C

in a randomized trial to all patients with malignant pleocytosis in a daily

regimen for 10 days, with simultaneous systemic chemotherapy. In addition,

a randomized schedule of “prophylactic” intrathecal chemotherapy is being

administered to patients with stage I-Ill disease.

The observation of peripheral neuropathy and malignant pleocytosis in

Burkitt’s lymphoma is very similar to the neurologic findings in “meningeal

leukemia.” This complication has been noted in patients with acute lympho-

blastic leukemia at any stage of the disease including complete hematological

remission and is characterized by signs of increased intracranial pressure and

peripheral or cranial neuropathy.1215 Treatment with intrathecal methotrexate,

and irradiation of the CNS have resulted in temporary remissions but invariable

recurrence.14 Our experience with Burkitt’s lymphoma has been similar, al-

though paraplegia and cranial neuropathies dominate the clinical picture, while




CNS INVOLVEMENT IN BUBKITT’S LYMPHOMA 727

signs or symptoms of increased intracranial pressure are infrequent. Malignant

pleocytosis occurs in approximately the same frequency as it is encountered in

acute lymphatic leukemia, and responds sensitively to intrathecal chemo-

therapy. Moreover, patients with Burkitt’s lymphoma may develop neurological

relapse while otherwise in complete remission.

Recently, evidence for an active immunological anti-tumor response in pa-

tients with Burkitt’s lymphoma has been reported.16 The finding of CNS in-

\�olvement in treated patients with Burkitt’s lymphoma who are otherwise in

complete remission suggests that an immunological as well as a pharmaco-

logical barrier exists in the CNS. Nervous tissue is virtually devoid of lymphoid

tissue and host surveillance mechanisms may be ineffective in this environment.

At some future date, when more quantitative immunological information is

available, specific and nonspecific immunotherapy may play an important sup-

plementary role in the treatment of Burkitt’s lymphoma and may substantially

assist in the management of patients with CNS involvement.

ACKNOWLEDGMENT

The authors wish to thank Professor S. K. Kyalwazi for performing the biopsies and

for assistance in the clinical care of the patients, and Mr. A. Kisuule and Mr. J. Mafigiri

for patient follow-up. Mr. J. Wamboka provided technical assistance. Grateful acknowledg-

ment is extended to medical officers of upcountry districts of Uganda for referring their

patients to the Lymphoma Treatment Centre. All chemotherapeutic agents used in thisstudy were supplied by the Cancer Chemotherapy National Service Center, National Cancer

Institute, Bethesda, Md.

REFERENCES

1. Clifford, P., Singh, S., Stjernsward, J.,and Klein, G.: Long-term survival of pa-

tients with Burkitt’s lymphoma: An assess-

ment of treatment and other factors which

may relate to survival. Cancer Res. 27:2578,

1967.

2. Cockshott, W. P., and Evans, K. T.:

Childhood paraplegia in lymphosarcoma

(Burkitt’s tumor). Brit. J. Radiol. 36:914,

1963.

3. Frank, G. L.: Involvement of the

nervous system in Burkitt’s tumor. In Clif-

ford, P., Linsell, A. A., and Timms, C. L.

(Eds.): Cancer in Africa. Nairobi, Kenya,East African Publishing House, p. 251.

4. Janota, I.: Involvement of the nervous

system in malignant lymphoma in Nigeria.

Brit. J. Cancer. 20:47, 1966.

5. Odeku, E. L., and Osuntokun, B. 0.:

The clinical neurology of Burkitt’s neoplasm.A preliminary evaluation based on 105 cases.

W. Afr. Med. J. 27:263, 1968.

6. Wright, D. H.: Burkitt’s tumor. A postmortem study of 50 cases. Brit. J. Surg.

51:245, 1964.

7. Ziegler, J. L., Morrow, R. H., Fass, L.,

Kyalwazi, S. K., and Carbone, P. P.: Treat-ment of Burkitt’s lymphoma with cyclophos-phamide. Cancer. 26:94, 1970.

8. Skeel, R. T., Yankee, R. A., andHenderson, E. S.: Meningeal leukemia: Two

simple methods for the rapid detection ofmalignant cells in the spinal fluid. JAMA

205:863, 1968.

9. Thomas, L. B., Chirigos, M. A.,

Humphreys, S. R., and Goldin, A.: Develop-

ment of meningeal leukemia (L1210) dur-

ing treatment of subcutaneously innoculatedmice with methotrexate. Cancer. 17:352,

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10. -, -, -, and -: Pathology of the

spread of L1210 leukemia in the centralnervous system of mice and effect of treat-ment with cytoxan. J. Nat. Cancer Inst.

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11. -: Pathology of leukemia in the

brain and meninges. Post mortem studies of

patients with acute leukemia and of micegiven innoculations of L1210 leukemia.

Cancer Res. 25:1555, 1965.




728 ZIEGLER ET AL.

12. Haghbin, M., and Zuelzer, W. W.:A long-term study of cerebrospinal leukemia.

J. Pediat. 67:23, 1965.

13. Shaw, R. K., Moore, E. W., Freireich,E. J., and Thomas, L. B.: Meningeal

leukemia. A syndrome arising from increasedintracranial pressure in patients with acuteleukemia. Neurology (Minneap.) 10:823,

1960.14. Sullivan, M. P., Vietti, T. J., Fern-

bach, D. J., Griffith, K. M., Haddy, T. B.,and Watkins, W. L.: Clinical investigations

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trexate. Blood 34:301, 1969.

15. Whiteside, J. A., Philips, F. S.,Dargeon, H. W., and Burchenal, J. H.:Intrathecal aminopterin in neurologicalmanifestations of leukemia. Arch. Intern.

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16. Fass, L., Herberman, R. B., and

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1970 36: 718-728

CARBONEJOHN L. ZIEGLER, AVRUM Z. BLUMING, RICHARD H. MORROW, JR, LEROY FASS and PAUL P. Central Nervous System Involvement in Burkitt's Lymphoma

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central nervous system involvement in burkitt's lymphoma - blood

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